BMP7 is an essential progenitor cell maintenance factor. The parent project examines the role of BMP7 signaling from progenitors to stroma in regulating progenitor differentiation. The proposed revision extends these investigations to studies of the direct effects of BMP7 on progenitors and makes use of a novel cell- based technique to explore challenging questions regarding regulatory signaling within the progenitor cell niche. Through addition of the study of direct effects of BMP7 on progenitors, the scope of the parent grant will be expanded, and through use in the competitive revision of a cell-based technique to study the progenitor niche, which was developed under the parent grant, the pace of the overall research program will be accelerated. We present preliminary data showing that BMP7 activates Jun kinase (JNK) via TGF2 activated kinase 1 (TAK1) directly in nephron progenitors rather than Smad-mediated signaling and that this signal promotes proliferation. BMP7 thus acts through JNK as a proliferation factor in nephron progenitors. Our in vivo studies demonstrate that once nephron progenitors begin to differentiate, Smad-mediated signaling commences in these cells. Interestingly, low levels of nuclear Smad transcription factors can be detected in nuclei of nephron progenitors, and it is thus most likely that a specific mechanism inhibits the Smad-mediated transcriptional response in these cells. On the basis of these findings, we hypothesize that BMP signaling functions bimodally in nephrogenesis, promoting self renewal of nephron progenitors through a JNK mediated response, and promoting nephron differentiation through a Smad mediated response. Intracellular factors inhibiting Smad mediated signaling may function as the switch between these two signaling outcomes. We propose to investigate this dynamic model for progenitor cell regulation by adding two new specific aims to the parent project: 1) Understanding the mechanism inhibiting Smad mediated transcriptional responses to BMP7 in nephron progenitors, and determining the consequences of bypassing this regulation. 2) Determining the consequences of inactivating the signaling pathway mediating BMP7-induced progenitor cell proliferation in vivo. PUBLIC HEALTH RELEVANCE: Chronic kidney diseases are common and debilitating, often with limited treatment options. Advances in experimental cell based therapies have demonstrated that it is possible to grow new kidney tissue in the adult from embryonic progenitor cells. The aim of this study is to understand pathways that regulate these kidney progenitor cells, in order to advance the development of cell based therapies for kidney disease.